Therapy/Treatment of Systemic Sclerosis

By Daniel Furst, M.D. (originally published in "Scleroderma Voice," Winter 2000–2001)

Evidence supporting a genetic basis for systemic sclerosis (SSc) is found in family data, where several cases of SSc are associated with a number of other connective-tissue diseases. Examination of the genetics of the TSK mouse reveals a mutation of chromosome 1, possibly in the col 3 alpha-1 gene.

The environment can also be a factor

A number of external stimuli have been associated with systemic sclerosis. These include such disparate environmental factors as

• organic solvent;
• L-tryptophan; and
• graft-versus-host disease.

Genes and environment both contribute

Genetic and environmental factors combine to stimulate the immune system. Evidence supporting the activity of the immune system is relatively abundant. Approximately 95% of SSc patients have positive ANA in their sera, and soluble interleukin 2 receptor is increased in patients with fatal SSc.

The impact of immune-system stimulation

The immune mediators released by the immune system stimulate scleroderma fibroblasts.

Not only does an activated immune system stimulate fibroblast proliferation, but it can damage the endothelium.

In fact, SSc serum is cytotoxic to the endothelium. Anti-Endothelial Cytotoxic antibodies in SSc correlate with digital ulcerations, interstitial lung disease, and decreased renal (kidney) function.

When damaged, the endothelium activates the immune system by releasing intracellular adhesion molecules and endothelium lymphocyte adhesion molecules, thus amplifying immune activation.

In turn, this results in lymphocyte adherence, diapedesis, and increased immune damage.

Interrupting the pathogenetic cycle

All that remains to close the pathogenetic circle is to show that collagen can cause immunological activation.

It is reasonable to approach the treatment of systemic sclerosis by trying to interrupt the pathogenetic cycle. For example, treatment might be aimed at

• addressing the vascular damage;
• preventing fibrosis; or
• suppressing the immune response.

Results of recent clinical drug trials

Trial of a prostacyclin-derivative

A 12-week randomized trial of a prostacyclin derivative, infused into patients with systemic sclerosis and pulmonary hypertension, showed only small changes in pulmonary artery pressure and pulmonary vascular resistance.

There was a decrease in fatigue and dyspnea (shortness of breath, difficult or labored breathing), and an increase in the distance patients were able to walk in six minutes.

Two iloprost trials

A double-blind trial of intravenous iloprost infusions was positive, but a double-blind trial using iloprost orally was negative.

To date, interrupting this step in the pathogenetic cycle of systemic sclerosis has been only minimally effective.

Interferon gamma

A trial using interferon gamma to treat interstitial pulmonary fibrosis in idiopathic pulmonary fibrosis significantly improved pulmonary function tests in the interferon gamma-treated patients compared to the controls used in the study.

Relaxin

[We have omitted Dr. Furst's discussion of the preliminary investigations of Relaxin, in view of the fact that Connetics Corporation discontinued its Phase III Relaxin Trials on Oct. 8, 2000 due to disappointing results. —Editor]

D-penicillamine

A study of low-dose D-penicillamine (62.5 mg daily) to high-dose D-penicillamine (750 mg daily) examined patients with early diffuse systemic sclerosis.

No changes were found in skin score, mortality, or the incidence of renal crisis in the trial.

It is highly unlikely that D-penicillamine is effective in systemic sclerosis, either to decrease fibrosis or as an immunosuppressive agent.

There is slowly accumulating evidence that fibrosis can be reversed, or at least stabilized in systemic sclerosis, though more data and evidence still need to be accrued.

Chlorambucil

A trial examining chlorambucil versus placebo in systemic sclerosis patients was one of the first well-controlled trials to test the importance of the immune system in SSc.

This negative trial was flawed by the use of patients with both diffuse and limited disease and the entry of patients with relatively late systemic sclerosis (7.9 years).

Cyclosporin A

Cyclosporin A is a medication which is relatively selective for T-cell suppression.

A small open trial showed improvement in skin score, but was associated with nearly universal decreased renal (kidney) function.

While a double-blind trial of Cyclosporin A is still awaited its toxicity is unlikely to make Cyclosporin a very useful treatment.

Methotrexate

A double-blind, randomized placebo-controlled crossover trial of methotrexate in systemic sclerosis used a logical, but complex definition of improvement.

This trial showed improvement in 63% of methotrexate-treated patients versus 17% of placebo-treated patients.

Cyclophosphamide

Cyclophosphamide is an effective, alkylating immunosuppressive which has been used to decrease both B-cell and T-cell function.

A trial showed that in patients with alveolitis by bronchoalveolar lavage, cyclophosphamide seemed to improve or stabilize pulmonary function.

Among patients with BAL-proven alveolitis, cyclophosphamide resulted in improvement or stabilization of disease in 15 of 17 patients.

In contrast, out of 11 patients without alveolitis, seven patients stabilized and four worsened (none improved).

Summary of results of recent clinical drug trials

These trials, in general, seem to encourage the use of immunosuppressive agents to treat systemic sclerosis, but none of them is definitive. In most cases, some improvement was noted in some patients but cure never occurred.

Stem cell transplantation: risks and rewards

A more definitive test of the usefulness of immunosuppression for systemic sclerosis would be a trial of stem cell transplantation (SCT).

If stem cell transplantation, which nearly totally abbrogates the immune system, did not successfully treat selected patients with systemic sclerosis, it would be hard to recommend immunosuppressive therapy for the disease.

SCT is a very dangerous procedure. Only patients with the most progressive systemic sclerosis (whose prognosis is predictably poor) would be appropriate for such a procedure.

Selection criteria for SCT

Criteria include the presence of pre-defined amounts of skin involvement, disease duration (3 years), pre-defined internal organ involvement, and the lack of a number of well-defined exclusion criteria which would make SCT so dangerous that patients might not survive.

Forty-one procedures have been done in SSc patients worldwide. A limited number of mobilization regimens, conditioning regimens, and purging regimens were used.

Results of SCT to date

Results have been encouraging, but there has been near a 25% mortality rate. Deaths among SCT-treated patients included three who died during mobilization, two who died secondary to disease progression, and two who died secondary to regimen-related toxicity.

Of eight patients in a Seattle cohort with at least one-year follow-up, six showed marked improvement, with 30% improvement in the skin score and four out of five who returned, or were preparing to return, to work. Two patients died from what was believed to be regimen-related toxicity, but the treatment regimen has since been altered and the next 10 patients have not, thus far, developed the previous regimen-related toxicity.

Conclusions

The treatment of SSc remains difficult, although there is an increasing number of potentially effective regimens.

There is limited evidence supporting the use of prostacyclin derivatives to treat systemic sclerosis, some evidence that antifibrotic regimens may be effective, and moderate evidence that immunosuppression may be effective, at least in certain stages of this disease.

While we can be hopeful, only well-controlled, multi-center studies can eventually result in effective therapy for SSc. We strongly encourage this approach.

Daniel Furst, M.D., is the editor, with Philip Clements, M.D., of the authoritative medical text. Systemic Sclerosis (published by Williams & Wilkins).

We thank Dr. Furst and the Scleroderma Association of British Columbia, a sister organization of the Scleroderma Foundation, for allowing us to print this version of a speech given by Dr. Furst.

Note: In one or two instances. Dr. Furst's discussion differs slightly from Dr. Feghali's article in this issue. The explanation is that Dr. Furst's speech was given five months before the American College of Rheumatology meeting in November, on which Dr. Feghali 's article is based.

For example, Dr. Furst cites a nearly 25% mortality rate for the stem cell transplantation procedure, but notes, "The treatment regimen has since been altered and the next 10 patients have not, thus far, developed the previous regimen-related toxicity. " Indeed, in Dr. Feghali's report composed after the November ACR meeting, she notes an overall 20% mortality rate for the stem cell transplantation procedure, which represents a significant improvement. —Editor.